The concerns of a gathering of medical whistleblowers who attended a roundtable on May 15 were reported in the July 2005 issue of PLoS Medicine (http://medicine.plosjournals.org) by investigative journalist Jeanne Lenzer, who concluded that the pharmaceutical industry’s synchrony with the U.S. health care industry may be compromising medicine’s integrity.

Roundtable attendee David Graham, of the US Food and Drug Administration summed up his position by stating "The pharma-FDA complex has to be dismantled, and the American people have to insist on that, otherwise we're going to have disasters like Vioxx that happen in the future."

Other members of the gathering included Allen Jones, formerly of the Pennsylvania office of the Inspector General; Stefan Kruszewski, formerly of the Bureau of Program Integrity in the Pennsylvania Department of Public Welfare, Kathleen Slattery-Moschkau, who wrote and directed the film Side Effects, and an anonymous pharmaceutical industry researcher.

Jones reported that he filed a civil rights lawsuit in 2002 "to preserve my job and my right to speak out,” on his discovery of an account into which pharmaceutical companies were making deposits that was accessible by state officials responsible for writing guidelines for the treatment of patients in the state system. The officials "were given unrestricted educational grants that were deposited into an off-the-books account," according to Jones, who was removed from his position for talking to the press.

Stefan Kruszewski was also terminated from his position after uncovering abuse and fraud in the Pennsylvania Department of Public Welfare Bureau of Program Integrity.

In Kathleen Slattery-Moschkau’s film, she presented a fictionalized account of her experiences as a pharmaceutical representative, a job she resigned from after witnessing disturbing marketing practices.

In an editorial in the same issue of PLoS Medicine, the authors called the picture that emerged “deeply troubling" and voiced the hope that the report will encourage discussion.

—D Dye

May 27, 2005

Brain arachidonic acid associated with depression

Writing in the June 2005 Journal of Lipid Research, Pnina Green of Tel Aviv University and colleagues reported that a line of rats that exhibit signs of depression have higher brain levels of arachidonic acid, an omega-6 fatty acid, than normal mice.

Recent research has shown that a deficiency of omega-3 fatty acids may be a culprit in depression, as depressed patients have been found to have lower omega-3 blood levels than non-depressed individuals. Dr Green explained, "The ‘phospholipid hypothesis’ of depression postulates that decreased omega-3 fatty acid intake, and hence, perhaps decreased brain omega-3 fatty acid content, could be responsible for the disease. In humans, because of high dietary variability and the obvious inability to examine brain tissue, the theory is backed up mainly by indirect evidence."

In the current study, Dr Green and colleagues found that the brains of rats bred to exhibit characteristics of depression had similar levels of omega-3 fatty acids, but higher levels of the omega-6 fatty acid arachidonic acid. Arachidonic acid was 21 percent higher in the hypothalamus than in the brains of control rats, 24 percent higher in the nucleus accumbens, 31 percent higher in the prefrontal cortex, and 23 percent higher in the striatum. The discovery suggests that the balance between omega-3 and omega-6 fatty acids may be altered in depression.

"The finding that in the depressive rats the omega-3 fatty acid levels were not decreased, but arachidonic acid was substantially increased as compared to controls is somewhat unexpected," Dr. Green stated. "But the finding lends itself nicely to the theory that increased omega-3 fatty acid intake may shift the balance between the two fatty acid families in the brain, since it has been demonstrated in animal studies that increased omega-3 fatty acid intake may result in decreased brain arachidonic acid."

In a letter published in the May 26 2005 issue of Nature (www.nature.com) researchers at Washington University School of Medicine in St. Louis suggest that an underlying cause of atherosclerosis could be problems with the mitochondria of the cells in the vessel walls. Mitochondria are the cells' energy producing organs, which also create a signficant amount of oxidative stress. The presence of cardiovascular disease in individuals in whom risk factors such as high cholesterol are lacking has motivated scientists to investigate other mechanisms of the disease.

The research team, led by Professor of Medicine Clay F Semenkovich, MD, engineered mice to express uncoupling protein-1 in the aorta wall, anticipating that the protein could protect the animals from high blood pressure and atherosclerosis based on findings from previous research. Uncoupling protein converts energy from calories into heat and creates a similar effect as exercise in skeletal muscle. Expression of the protein was induced by administration of an antibiotic that causes atherosclerosis in mice.

Because mitochondria generate free radicals during the production of energy, the researchers believed that with less energy there would be less damage. However, rather than being protected, the mice developed hypertension and atherosclerosis. Dr Semenkovich explained, "The cells in the blood vessel wall apparently were trying to compensate for their less powerful mitochondria. It is possible that the decreased energy stores induced by the uncoupling protein caused cells to move more oxygen through the system. But the increased flux of oxygen through the blood vessel wall caused oxidative damage, high blood pressure and atherosclerosis."

Dr Semenkovich hypothesized that the same process may occur in aging humans, and that a deficiency of essential fatty acids could cause the changes in blood vessel wall metabolism. "It would be interesting to figure out how to take essential fatty acids, get them into the vessel wall and see if you could treat atherosclerosis that way," he stated.

At the annual meeting of the American Urological Association, held in May, Martha K Terris, MD, of the Veterans Affairs Medical Center in Augusta, Georgia reported that being obese or having a small prostate gland increase the risk of developing an aggressive form of prostate cancer.

Dr Terris and her colleagues evaluated the association between body mass index and prostate cancer in 787 men whose prostate glands were biopsied. They found that obesity was associated with a greater risk of prostate cancer, and also increased the risk of developing an aggressive cancer. The finding is controversial, because the hormone changes that occur with obesity decrease the hormone testosterone, which fuels prostate cancer growth. A reduction in testosterone would theoretically decrease prostate cancer risk. However, it appears that there is an association between obesity and aggressive cancers that are not testosterone-dependent.

In another study, Dr Terris’ team analyzed data from 1,106 men with prostate cancer who had their prostate glands removed, and found that those whose glands were smaller had a greater risk of aggressive disease. Dr Terris explained, “If you have a large prostate, cancer can grow to a fairly large size before it outgrows the surrounding prostate and spreads out into other areas of the body. However, if the prostate containing the cancer is small, the cancer does not have to grow very much before it is big enough to spread outside the gland.” She added, “Similar to the findings in obese men with prostate cancer, the explanation may be differences in hormone levels. If you have estrogen or less testosterone in your system, your prostate will not be as large as a man with a high testosterone because these hormones affect both benign prostate growth and cancer. As a result, the same hormone balance that result in a small prostate gives hormone insensitive tumors more chance to grow.”

—D Dye

May 18, 2005

HCA slows glucose uptake

A sudy published in the June 2005 issue of the American Journal of Physiology-Gastrointestinal and Liver Physiology (http://ajpgi.physiology.org/) revealed that hydroxycitric acid (HCA), the active ingredient in the fruit Garcinia cambogia used in traditional Indian medicine, helps slow glucose uptake after a meal, which reduces insulin output.

Researchers in the Netherlands administered HCA to rats before infusing sugar into their stomachs to mimic a meal. A control group of rats received no HCA before the infusion. The rats that received HCA were found to experience a much slower elevation in blood glucose after the sugar infusion than rats that did not receive the compound. HCA was also found to lower the rise in glucose following sugar administration after the compound was administered directly into the stomach or small intestine, which excluded the possibility that HCA had effected gastric emptying.

Lead author Peter Y. Wielinga elaborated, "Sugar that is normally absorbed rather quickly -- within about 20 minutes -- took over 2 hours after HCA ingestion. This delay is good because it reduces the high peaks of glucose, which otherwise would require the body to produce a lot of insulin to deal with the 'meal."

Dr Wielinga stated that the next step is to discover HCA's mechanism of action. He speculated, "If we can reduce the peaks and valleys of insulin with HCA, then it might have some application in diabetes, both in slowing progression to diabetes 2 and since these people have an obesity problem, it could potentially have an additional benefit in the therapeutic field. "

Dr Wielinga, who will be conducting research at the University of Zurich, also plans to investigate HCA's effect on reducing food intake, a phenomenon that has been observed in rodents.

—D Dye

May 16, 2005

Vitamin D therapy boosts drug's effect on prostate cancer survival

The 41st annual meeting of the American Society for Clinical Oncologists was the site of a presentation on May 15 by Christopher Ryan, MD of Oregon Health and Science University (OHSU) of the discovery that a high dose calcitriol drug called DN-101 extends the lives of advanced prostate cancer patients when given with docetaxel (Taxotere), the drug approved as the standard of care for androgen-indpendent prostate cancer (AIPC). Calcitriol is the biologically active form of vitamin D which, when administered, produces much higher blood levels of vitamin D than can be attained by diet or supplements.

The discovery is the outcome of the AIPC Study of Calcitriol Enhancing Taxotere (ASCENT), a randomized, double-blind, placebo-controlled clinical trial which tested the combination on 250 men with androgen-independent prostate cancer from September 2002 through January 2004. Dr Ryan's team found that DN-101 enabled the men to live 7.1 more months than those who received docetaxel alone, without producing any greater toxicity. Analysis of the data determined that the addition of calcitriol conferred a 49 percent increase in survival over the course of the study compared to men given docetaxel alone.

Tomasz Beer, MD, who is the national leader of the ASCENT trial, commented, "The data strongly suggest that DN-101, given in combination with docetaxel, will provide a substantial survival benefit to prostate cancer patients without adding toxicity. While we've known about the antitumor potential of vitamin D, toxicity has been a significant issue to be overcome in making it a successful part of prostate cancer therapy."

Dr Beer added. "Our results demonstrate that DN-101 has the potential to improve outcomes for patients and that moving forward with development of the drug is the right thing to do."

—D Dye

May 13, 2005

Tocotrienols lower cholesterol

Mohammad Minhajuddin, PhD, of the University of Rochester, and colleagues reported in the May 2005 issue of Food and Chemical Toxicology that tocotrienols from rice brain oil significantly lower total and low-density lipoprotein cholesterol (LDL). Tocotrienols are four of the eight members of the vitamin E family, whose benefits have only recently been explored.

Dr Minhajuddin's team fed rats a diet designed to induce atherosclerosis which more than doubled their cholesterol levels, tripled their triglyceride levels, and increased their LDL cholesterol by a factor of five after three weeks. Markers of oxidative damage were also increased. The animals were then given varying doses of tocotrienol rich fraction from rice bran oil for one week.

It was found that administration of tocotrienols lowered cholesterol dose-dependently, with the greatest benefit observed at a daily dose of 8 international units (IU) per kilogram, which is equivalent to a dose of 560 IU for a 154 pound human. Total cholesterol levels were lowered by 42 percent, and LDL cholesterol by 62 percent. HMG-CoA reductase, an enzyme that is used by the liver to make cholesterol, was reduced during treatment with tocotrienols, as well as two of the markers of oxidative damage.

Prior to the current study, Dr Minhajuddin conducted a small trial in which human volunteers who received 8 IU per kilogram per day tocotrienols experienced a 10 percent reduction in total cholesterol and a 26 percent reduction in LDL. He also conducted research that demonstrated that tocotrienol rich fraction reacts with liver enzymes to help eliminate toxins from the organ, as well as reducing liver tumors.

Because tocotrienols have not been found to cause any adverse effects, future research may determine whether they might be a viable alternative to statin drugs, which can have undesirable side effects.

The May 11 2005 issue of the Journal of the American Medical Association (http://jama.ama-assn.org/) published the results of a meta-analysis of 12 clinical trials involving vitamin D supplementation in the prevention of fracture, which concluded that supplementation with higher doses of vitamin D reduces the risk of hip and nonvertebral fractures in older individuals. The commonly recommended 400 international unit (IU) dose appeared to be insufficient for fracture prevention.

Vitamin D and calcium are recommended to help prevent osteoporosis, a disease characterized by weak, brittle bones, which leads to fractures and other complications, and is commonly diagnosed in older women.

Researchers from Harvard and other centers in Boston selected five randomzied clinical trials of vitamin D in the prevention of hip fracture and 7 which tested the vitamin's ability to prevent nonvertebral fracture risk. The combined studies included a total of 19,114 men and women aged 60 and older. The trials used the form of the vitamin known as cholecalciferol, or vitamin D3, which, according to studies cited in the current review, may be three times as potent as ergocalciferol, the dietary form of the vitamin.

The team found that doses of 700 to 800 international units vitamin D per day reduced the risk of hip fracture by 26 percent and nonvertebral fracture by 23 percent. Of the studies that used 400 IU vitamin D, no significant benefit was observed for either type fracture.

The authors state that although the role of additional calcium supplementation could not clearly be defined from the studies, at least 700 milligrams calcium per day may also be necessary for nonvertebral fracture prevention. They recommend that future research compare higher doses of vitamin D, and that scientists determine whether and in what dose calcium increases vitamin D's ability to help prevent fractures.

—D Dye

May 9, 2005

Diets high in folate linked with lower risk of prostate cancer

The April 2005 issue of the American Association for Cancer Research journal Cancer Epidemiology, Biomarkers & Prevention (http://cebp.aacrjournals.org/) published the findings of Italian researchers that a greater intake of folate is associated with a reduced risk of developing prostate cancer. Folate is the form of the B vitamin folic acid that naturally occurs in foods, particularly leafy green vegetables.

The current study utlized data from a case-control study of prostate cancer conducted between 1991 and 2002 in which 1,294 patients with prostate cancer were compared with 1,451 patients without cancer who were admitted to the same network of hospitals. Dietary information gathered from interviews during which the participants were asked about their intake of 78 different foods during the two years prior to their diagnosis or hospital admission was analyzed for folate and other nutritional levels.

Analysis of the data determined that folate intake was inversely related to prostate cancer risk. Men in the top one-fifth of folate consumption had a 34 percent lower risk of prostate cancer than that experienced by men whose folate intake was in the lowest fifth. This relathionship was consistent among men of all ages. When men whose intake of folate was high and alcohol consumption was low were compared to those whose intake of folate was low and alcohol consumption high, they were found to have a 54 percent lower risk of the disease.

The authors discuss two mechanisms which explain low folate's relationship to an increase in cancer. First, a deficiency of the vitamin decreases S-adenosylmethionine (SAMe), which can lead to DNA hypomethylation and increase the activation of genes that promote cancer. The other explanation for folate's benefit is that a deficiency can cause an error in DNA synthesis that results in breaks in the chromosomes which increase cancer risk.

—D Dye

May 6, 2005

Higher vitamin B6 means lower colorectal cancer risk for women

A study published in the May 4 2005 of the Journal of the National Cancer Institute found that having a relatively high intake of vitamin B6 or having high levels of the vitamin in the blood was associated with a lower risk of deveveloping colorectal cancer.

Esther K. Wei, ScD, from Brigham and Women's Hospital and Harvard Medical School, and colleagues examined data from women who participated in the Nurse's Health Study, which followed 121,700 nurses between the ages of 30 and 55 upon enrollment. The current study analyzed blood samples drawn in 1989 from 32,826 women in 1989 and food frequency questionnaires completed in 1980, 1984, 1986 and 1990. The blood samples were assayed for pyridoxal 5'-phosphate, the main circulating form of vitamin B6, which is necessary for DNA synthesis and methylation--processes that can be involved in the development of colorectal cancer.

From 1989 to 2000, 194 cases of colorectal cancer were diagnosed. Women whose vitamin B6 levels were in the top one-fourth of participants had a 44 percent lower risk of colorectal cancer than those whose levels were in the lowest quarter. The risk of colon cancer specifically was even lower, with a 58 percent reduction experienced by women in the highest quarter of plasma B6. Dietary intake of vitamin B6 was also inversely associated with the risk of developing colorectal cancer. Thirty-three cases of colorectal cancer were identified among women whose intake was in the top 25 percent compared to 59 in the lowest -fourth.

Vitamin B6 is involved in over 100 physiologic processes, including the conversion of homocysteine to cysteine and the regeneration of a form of folic acid involved in DNA synthesis, both which can be involved in the development of cancer.

—D Dye

May 4, 2005

Vitamin C offsets damage to unborn caused by smoking

A study published in the May 1 2005 issue of the the American Journal of Respiratory and Critical Care Medicine found that vitamin C provided protection to primate infants born to mothers exposed to nicotine. Thousands of children are born each year to mothers who fail to quit smoking during their pregnancy. Exposure of a fetus to maternal cigarette smoking can cause premature delivery, growth retardation, reduced pulmonary function and even death in newborn infants.

Eliot Spindel, MD, PhD and colleagues at the Oregon National Primate Research Center, Oregon Health & Science University gave daily doses of nicotine to monkeys during pregnancy and supplemented some of them with 250 milligrams vitamin C per day. An additional group of monkeys received neither nicotine nor vitamin C. Dr Spindel, who is the study's senior author, explained the outcome: "We found that animals exposed to nicotine prior to birth had reduced air flow in the lungs compared to animals that were given nicotine and vitamin C. In fact, the nicotine plus vitamin C group had lung air flow close to that of a normal animal."

Although vitamin C appeared to protect the lungs, it did not protect against other effects of fetal nicotine exposure such as reduced body weight and abnormal brain development. Dr Spindel noted, "The findings of this research are highly applicable to humans. The sad reality is that approximately 11 percent of pregnant mothers continue to smoke during pregnancy -- this translates to about a half a million American women a year . . . While this research finding may assist the babies of these mothers, it does not make smoking during pregnancy more acceptable. It would only become a last resort treatment when an expectant mother is unwilling to stop smoking."

—D Dye

May 2, 2005

Fiber supplement improves lipids

The American Heart Association's Sixth Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology was the site of a presentation by Peter J. Verdegem, PhD on April 30, 2005 of his team's findings that supplementing with fiber can lower low-density lipoprotein (LDL) cholesterol and raise high-density lipoprotein (HDL) in diabetics. Diabetes is associated with the development of cardiovascular disease, for which disordered lipids are a risk factor. Research has shown that increasing the amount of fiber in the diet can help reduce cholesterol. The current study is among the first to evaluate fiber's effect diabetics' cardiovascular risk reduction for type 2 diabetes.

Seventy-eight individuals with type 2 diabetes received 5 grams of a supplement containing soluble and insoluble fiber before two to three meals per day for ninety days. The supplement consisted of guar gum, gum arabic, locust bean gum, pectin and oat fiber dispersed in calcium carbonate. Total, LDL and HDL cholesterol and triglycerides were measured at the beginining and end of the study.

At the study's conclusion, the participants' average total cholesterol had declined by 14.4 and triglcyerides were similarly reduced. While LDL cholesterol dropped by 28.7 percent to an average of 92 milligrams per deciliter, HDL rose by 21.8 percent to 55 mg/dL. Dr Verdegem, who is the chief science officer at Unicity International in Orem, Utah, explained, "The product was designed to fill that gap between the real intake and the advised intake. When it is in the intestines, the fiber decreases reabsorption of cholesterol from a meal."

He concluded,"The remarkable observation is that this works on two sides: It decreased LDL and increased HDL by significant amounts at 90 days. This approach is virtually free of side effects. It opens up an alternative treatment option."

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